This translational proposal uses a rapid desensitization approach to develop a safe, effective and rapid way to suppress human IgE-mediated disease. We can already safely, rapidly desensitize mice to all antigens (Ags) by injecting them hourly with doubling doses of an anti-FcRI monoclonal antibody (mAb), starting with a dose too small to elicit a clinical reaction. Using this protocol to treat mice with an anti FcRI mAb that only binds FcRI that is not occupied by IgE: (1) rapidly induces short-lived suppression of IgE/FcRI signaling; and (2) slowly removes all mast cell membrane FcRI and IgE, even in mice that have high serum IgE levels. In mice, our approach is safer than rapid desensitization with Ag and can safely be maintained indefinitely by repeated injection of anti-FcRI mAb. We will now adapt this approach to humans, make it more rapid, and make it even safer. Aim 1 uses an anti-human (hu) FcRI mAb that has characteristics similar to our anti-mouse FcRI mAb to desensitize: (1) huIgE-treated transgenic mice that express huFcRI instead of mouse FcRI; and (2) immunodeficient NOD/SCID mice that lack the cytokine receptor common ? chain, express transgenic huSCF, huIL-3, and huGM-CSF and have been reconstituted with human cord blood cells (these mice secrete human IgE and generate human mast cells and basophils). We also modify our desensitization protocol to make it more compatible with potential human use by injecting anti-huFcRI mAb subcutaneously instead of intraperitoneally. Aim 2 accelerates desensitization with antihuFcRI mAb by using a commercially available mAb that removes all mast cell huFcRI, regardless of its IgE occupancy. We also generate our own mAb that has this property so that we can modify its structure in Aim 3. Aim 3 increases the safety of rapid desensitization with anti-huFcRI mAb. We further suppress any clinical reactions that might occur during rapid desensitization by: (1) inhibiting H1 and H2 receptors; (2) inhibiting the tyrosine kinase syk; and (3) engineering anti-FcRI mAb to bind more avidly to the inhibitory receptor, Fc?RIIb. Successful completion of these aims could provide a way to safely and rapidly protect against all FcRI-mediated disease.